Investigations were undertaken to determine other mechanisms of action that recombinant human interferon-alpha (rhIFN-alpha) may have in its ability to potentiate MRK16 monoclonal antibody (mAb)- mediated reversal of VCR resistance. In vitro results showed that rhIFN-alpha did not substantially modulate the expression of MRK16 epitopes or influence the rate of intracellular VCR accumulation when compared to MRK16 treated HT- 29mdr1 cells. Furthermore, in vivo studies suggest that the modulation of MDR in our model system is due to a direct effect of MRK16 mAb on Pgp function. Initiation of treatment 10 days following HT-29mdr1 transplantation with 250 mu g of MRK16 Igg2a or MRK16 F(ab')2 alone or in combination with rhIFN-alpha (5x10,000 U/ml) plus VCR (1 mg/kg) has resulted in no difference in survival between the two groups (80 days post-tumor). Other modalities of therapy, in regards to reversal of drug resistance, have shown that the administration of liposomal encapsulated VCR (LEVCR) 10 days after HT-29mdr1 tumor cell injection and then weekly for 3 weeks resulted in a highly significant increase in MST (60 days,p < .0001) when compared to mice treated with VCR alone (MST=38 days). The concomitant administration of a ribonuclease, Onconase, and VCR resulted in a significant increase in MST (69 days, p < .0001) when compared to mice treated with VCR (MST =43 days). Thus Onconase is able to overcome VCR resistance. Studies are currently underway to investigate the effect of MRK16 alone or in combination with rhIFN-alpha and either adriamycin or taxol using a human ovarian (OVCAR-3) and breast (MDA-231) tumor lines that express the MDR phenotype.